SCALING BASIC TOXICOKINETIC PARAMETERS FROM RAT TO MAN

Scaling of the quantified dispositional parameters of xenobiotics from animals to man is of interest from the standpoint of toxicology (e.g. , poisoning and risk assessment). Scaling is also important from the s tandpoint of therapeutics because it represents a strategy for predict ing first-use-in-human doses in clinical trials of investigational new drugs. Current strategies for scaling either doses of xenobiotics or the dispositional parameters of xenobiotics from animals to man rely o n models that take account principally of species differences in weigh t or body surface area Interspecies scaling of dispositional parameter s such as clearance or volume of distribution commonly involves the co mparison of estimates of these parameters for a given xenobiotic among numerous species On the basis of weight with the resultant mathematic al relationship used to predict the values of those parameters for tha t xenobiotic in a species weighing, on average, about 70 kg (i.e., a m an). Our approach has been to ascertain whether a useful mathematical model could be developed for predicting the dispositional parameters o f a xenobiotic, its half-life and volume of distribution, in humans ba sed exclusively on estimates of those parameters in rats. Based on a d ata set of about 100 different xenobiotics, we found that values for h alf-life and volume of distribution of a xenobiotic in humans can be p redicted from the estimates of those parameters in rats.